If you truly think this is a rare disease, it's very likely that there's just one single causal mutation in your partner's genome. The easiest way to find that is to:
1. Search for variants in that genome where the allele frequency is close to 0 in a very large population e.g. https://gnomad.broadinstitute.org/
Rare diseases are typically due to a coding mutation that alters the protein coding sequence in some significant way.
If you need help contact details are on my profile. I do this for a living at a university.
rsIDs are a minefield as they change often, there are synonyms and probably you won't have all loci properly annotated. Don't rely on that too much unless you really know what you are doing.
If it's not a rare disease, this gets quite more difficult. Also, depending on the whole genome sequencing platform you have used, many structural variants (e.g. deletions or insertions of large chunks of DNA) won't be easy to measure.
Other comments have suggested Promethease, which will give you a bit of help if it's not a rare disease (e.g. if it's an autoimmune one, it's good at imputing HLA and finding risk haplotypes).
My whole comment is a bit of an oversimplification, but I think these suggestions are a good starting point.
I haven't worked on this problem, but others in my graduate lab did. If you're interested in a tool that automates some of this process (takes VCF as input; filters variants based on frequency; you'll need to map disease symptoms/phenotypes to Human Phenotype Ontology [1] identifiers), some of my former lab mates developed a web tool [2]: https://amelie.stanford.edu/submit
Apologies for hijacking the top comment, I do not know where else to ask this and I found no local researchers:
My son was born 3 months ago with Poland syndrome. This came as a shock but it has also drawn me to look into the scientific literature.
While the common belief was that PS has no underlying genetic cause, there are papers suggesting that the may be.
Studying - I ran across many anomalies on my own body (his father), so minor that there were never considered relevant until now (I'm 40 and lead a normal life).
It would seem that on the right side of my body I have at least:
- A mild case of Becker's Nevus
- Single palmar crease
- A somewhat smaller shoulder blade (suggesting a Sprengel diformity?)
If the above is correct, this may be an opportunity (by studying my genome and my son's genome) to establish a link or a common cause for Becker Nevus Syndrome and Poland Syndrome - both fairly rare anomalies.
Can you suggest who may be interested in studying this?
This has no value for me or my son, however the scientific endeavour may be of value for the future.
I just wanted to wish you all the best. I really empathize. It felt unfair to discover the statistics on birth defects vs age of the parents -- there's almost a linear correlation between age and defects, and no one ever told me. I'll be 34 in Feb, and I've wondered many times whether I'd be a good dad if our kiddo pops out with a few missing pieces. (We're finally in a position where IVF is on the horizon, so it's a constant worry.)
It's incredibly inspiring to have an example like yours. Thank you so much for trying to connect with researchers to help them understand the disease, even though it "has no value for you or your son." Your attempt has a lot of value as a model to follow. I'll try to do the same thing if we end up in a similar position. Good luck!
My wife and i had kids at your age and 15 years on we're all doing very well. We know older parents, also doing well. We were told there were some risks increased for an older mother, but with hindsight these were small percentage chance of something to a slightly larger but still very small percentage. True, no one wants to be the rare bad case. If you're planning pregnancy, i think i recall it's good if the mother has Folic Acid, but I'm no scientist. https://www.cdc.gov/ncbddd/folicacid/about.html Good luck, I hope it works out.
A woman’s peak reproductive years are between the late teens and late 20s. By age 30, fertility (the ability to get pregnant) starts to decline. This decline becomes more rapid once you reach your mid-30s. By 45, fertility has declined so much that getting pregnant naturally is unlikely for most women.
Down syndrome (trisomy 21) is the most common chromosome problem that occurs with later childbearing. The risk of having a pregnancy affected by Down syndrome is
1 in 1,480 at age 20
1 in 940 at age 30
1 in 353 at age 35
1 in 85 at age 40
1 in 35 at age 45 [2]
My jaw dropped.
I probably shouldn't claim "birth defects" in the general sense, just Down syndrome specifically. But the wording of "most common chromosome problem" seems to imply that this is a pretty reasonable inference.
Had no idea I was risking my kiddo's health so much by waiting.
There is also Matchmaker Exchange who's aim is to be a clearing house where very rare diseases become slightly less rare when patients can locate someone else with the same thing. So an answer to who may be interested, could be someone else who has your symptoms.
Poland Syndrome may have links to other forms of syndactyly, so you maybe able to narrow down some of the patterns, which could include cultural diets or local environmental factors.
https://rarediseases.info.nih.gov/diseases/13181/syndactyly
/Edit**
This also explains a bit about gene regulation ie switching on & off and ramping them up or down
https://www.ncbi.nlm.nih.gov/books/NBK26872/
/Edit**
Clues would be looking at conditions with the same properties like webbing and if its exactly the same condition, treatments for these other conditions may become relevant.
There is a lot of studies on Google Scholar and it goes back to the 1800's. Some studies in livestock or vegetation (crops mainly) can also illicit clues because despite being different some chemical reactions or some end results will be the same in humans and animals and plants. You just cant change some of the chemical reactions, melatonin be one that is seen in humans, animals and plants, it increases in darkness.
Can confirm this, this was essentially what my first scientific article was about. If you choose to avoid rsID and use genomic location, remember that there are different versions of the human genome, and make sure to align it with gnomAD's version.
I work in an adjacent area and agree this is all good advice.
OP, how did you even get the sequence to begin with? I have a friend who has an immunodeficiency which is almost certainly due to a rare genetic disorder and want to do a very similar thing. Despite contacting his physician, fellow researchers, and even my institution's president -- with friend's full cooperation -- no one is willing to pay for it.
I'm at my wit's end to the point that I'm starting to think the only viable option is paying for it out of pocket, but it's not cheap.
A question you might want to ponder is: suppose you isolate the problem to a single missense/nonsense/truncation mutation in a protein that seems likely to cause the phenotype. How do you plan to use that information? In theory, there is gene therapy, but in reality, given how much effort I have had to go through just to get this fellow sequenced -- and I'm a PhD working in genomics with a lot of contacts -- creating a custom one-off gene therapy solution seems like it would be a very tremendous undertaking.
There is a very difficult problem here in that rare or "personalized" disease treatments are: A) not profitable, so drug companies have no interest, B) there are mountains of paperwork, IRBs, consent waivers, etc, involved in developing an experimental therapeutic, C) by definition you cannot do a proper clinical trial on a one-off, and D) it requires several different types of expertise to pull such a thing off. Sadly this means that it almost never happens, even though I suspect there are a lot of severe and lifelong genetic disorders which could be diagnosed and treated with technology available today.
Based on my experience so far, I suspect that even if you were to hand his physician very strong evidence that "the problem is caused by this specific single mutation", the response will be "OK, thanks". You should not make strong assumptions about them being able to take it from there. All this is based on the best-case scenario of it being a single variant in a coding region; if the disorder is caused by multiple variants at different loci, anything you find will probably not be actionable.
OP, how did you even get the sequence to begin with? [...] no one is willing to pay for it.
My neurologist ordered sequencing for me from Invitae, to determine the subtype of Ehlers-Danlos I have and rule out neuromuscular diseases. She said insurance usually covers it, and it's only a few hundred bucks if they don't. Invitae appears to do WGS for such panels. I've also heard of Nebula genomics offering affordable WGS and exome sequencing.
She said she'd take a look at the results, and if anything popped out as unusual, I'd see a geneticist.
A question you might want to ponder is: suppose you isolate the problem to a single missense/nonsense/truncation mutation in a protein that seems likely to cause the phenotype. How do you plan to use that information?
Identify the molecular pathway involved and see if there's any drugs available that might modulate it in a therapeutic way. You might also identify similar diseases that might share similar treatments, once you know the etiology.
Once a mutation or gene responsible is identified, other patients can be as well, which can slowly lead to mouse models and clinical trials etc.
This. It's not my field but I strongly suspect I have a troublesome mutation of some sort. If I was able to track it down what good would that do? (I almost certainly inherited it which is why I think it's genetic.) Sequencing isn't that expensive these days, I keep thinking about it but even if I found enough others to pin down the mutation what good would that do? "Success" would simply be an accurate diagnosis, nothing more.
Not OP, but I got my whole genome sequenced from sequencing.com. It is currently around 399 USD. The sequencing is done by Nebula Genomics, nebula.org, where it is currently 299 USD.
You get to keep all the raw data from the sequencing and you will get some reports included.
I did it in order to do a genetic disease screening as I was very sick with strange symptoms for a long time.
Thanks to you, and others, for sharing. I hadn't yet resorted to looking in the consumer space. In research (and presumably clinical)-land, the costs are substantially higher.
I'll be looking into it further to figure out whether there is some tradeoff here, or if it is just typical cost bloat for medicine/academia.
I haven’t done very thorough research, but my impression is that there is a considerable cost bloat if you go through hospitals and similar, but that the genome sequencing is essentially the same.
As an alternative to step 2, you could also score the filtered vcf file (this is key to get rid of most of the initially millions of variants) with a variant prioritization framework like CADD (cadd.gs.washington.edu) to immediately highlight 'interesting' variants. Highlighting certain genes can definetly help, though it is not always conclusive
(I do not want to demotivate but please be cautious. Even the best analysts have 'only' around 50% case-solve rate. If it is an adult-onset-disease, chances can be lower as the disease mechanism in that case may not be 'consequential' enough to be naturally selected against)
Comments
If you truly think this is a rare disease, it's very likely that there's just one single causal mutation in your partner's genome. The easiest way to find that is to:
1. Search for variants in that genome where the allele frequency is close to 0 in a very large population e.g. https://gnomad.broadinstitute.org/
2. Look into variant effects for those you prioritized in step 1 using https://www.ensembl.org/info/docs/tools/vep/index.html
Rare diseases are typically due to a coding mutation that alters the protein coding sequence in some significant way.
If you need help contact details are on my profile. I do this for a living at a university.
rsIDs are a minefield as they change often, there are synonyms and probably you won't have all loci properly annotated. Don't rely on that too much unless you really know what you are doing.
If it's not a rare disease, this gets quite more difficult. Also, depending on the whole genome sequencing platform you have used, many structural variants (e.g. deletions or insertions of large chunks of DNA) won't be easy to measure.
Other comments have suggested Promethease, which will give you a bit of help if it's not a rare disease (e.g. if it's an autoimmune one, it's good at imputing HLA and finding risk haplotypes).
My whole comment is a bit of an oversimplification, but I think these suggestions are a good starting point.
This advice is spot on!
I haven't worked on this problem, but others in my graduate lab did. If you're interested in a tool that automates some of this process (takes VCF as input; filters variants based on frequency; you'll need to map disease symptoms/phenotypes to Human Phenotype Ontology [1] identifiers), some of my former lab mates developed a web tool [2]: https://amelie.stanford.edu/submit
[1] https://hpo.jax.org/app/
[2] https://www.medrxiv.org/content/10.1101/2020.12.29.20248974v...
Apologies for hijacking the top comment, I do not know where else to ask this and I found no local researchers:
My son was born 3 months ago with Poland syndrome. This came as a shock but it has also drawn me to look into the scientific literature.
While the common belief was that PS has no underlying genetic cause, there are papers suggesting that the may be.
Studying - I ran across many anomalies on my own body (his father), so minor that there were never considered relevant until now (I'm 40 and lead a normal life).
It would seem that on the right side of my body I have at least:
If the above is correct, this may be an opportunity (by studying my genome and my son's genome) to establish a link or a common cause for Becker Nevus Syndrome and Poland Syndrome - both fairly rare anomalies.Can you suggest who may be interested in studying this?
This has no value for me or my son, however the scientific endeavour may be of value for the future.
I just wanted to wish you all the best. I really empathize. It felt unfair to discover the statistics on birth defects vs age of the parents -- there's almost a linear correlation between age and defects, and no one ever told me. I'll be 34 in Feb, and I've wondered many times whether I'd be a good dad if our kiddo pops out with a few missing pieces. (We're finally in a position where IVF is on the horizon, so it's a constant worry.)
It's incredibly inspiring to have an example like yours. Thank you so much for trying to connect with researchers to help them understand the disease, even though it "has no value for you or your son." Your attempt has a lot of value as a model to follow. I'll try to do the same thing if we end up in a similar position. Good luck!
My wife and i had kids at your age and 15 years on we're all doing very well. We know older parents, also doing well. We were told there were some risks increased for an older mother, but with hindsight these were small percentage chance of something to a slightly larger but still very small percentage. True, no one wants to be the rare bad case. If you're planning pregnancy, i think i recall it's good if the mother has Folic Acid, but I'm no scientist. https://www.cdc.gov/ncbddd/folicacid/about.html Good luck, I hope it works out.
Do you have any links about that?
I've never heard of this correlation and have friends that became parents at 50 so I am curious.
I know that the older you get, the riskier it is to have children, but had no idea it was a linear correlation.
It's ridiculously hard to discover. I tried to signal boost it at https://twitter.com/theshawwn/status/1441657590501445651 but depressing facts tend not to get much traction.
From https://news.ycombinator.com/item?id=28650922:
My jaw dropped.
I probably shouldn't claim "birth defects" in the general sense, just Down syndrome specifically. But the wording of "most common chromosome problem" seems to imply that this is a pretty reasonable inference.
Had no idea I was risking my kiddo's health so much by waiting.
Holy cow. That's pretty scary!
1 in 35 is a lot.
Thanks for that!
There is also Matchmaker Exchange who's aim is to be a clearing house where very rare diseases become slightly less rare when patients can locate someone else with the same thing. So an answer to who may be interested, could be someone else who has your symptoms.
https://www.matchmakerexchange.org/
Poland Syndrome may have links to other forms of syndactyly, so you maybe able to narrow down some of the patterns, which could include cultural diets or local environmental factors. https://rarediseases.info.nih.gov/diseases/13181/syndactyly /Edit** This also explains a bit about gene regulation ie switching on & off and ramping them up or down https://www.ncbi.nlm.nih.gov/books/NBK26872/ /Edit** Clues would be looking at conditions with the same properties like webbing and if its exactly the same condition, treatments for these other conditions may become relevant.
There is a lot of studies on Google Scholar and it goes back to the 1800's. Some studies in livestock or vegetation (crops mainly) can also illicit clues because despite being different some chemical reactions or some end results will be the same in humans and animals and plants. You just cant change some of the chemical reactions, melatonin be one that is seen in humans, animals and plants, it increases in darkness.
Just about any researcher who published on it. It’s not unusual to see an article describing single clinical case.
Can confirm this, this was essentially what my first scientific article was about. If you choose to avoid rsID and use genomic location, remember that there are different versions of the human genome, and make sure to align it with gnomAD's version.
This is awesome! I also do this for a living, tending more towards oncogenic side, but what you said is perfectly fine!
I'd also love to help OP :)
I work in an adjacent area and agree this is all good advice.
OP, how did you even get the sequence to begin with? I have a friend who has an immunodeficiency which is almost certainly due to a rare genetic disorder and want to do a very similar thing. Despite contacting his physician, fellow researchers, and even my institution's president -- with friend's full cooperation -- no one is willing to pay for it.
I'm at my wit's end to the point that I'm starting to think the only viable option is paying for it out of pocket, but it's not cheap.
A question you might want to ponder is: suppose you isolate the problem to a single missense/nonsense/truncation mutation in a protein that seems likely to cause the phenotype. How do you plan to use that information? In theory, there is gene therapy, but in reality, given how much effort I have had to go through just to get this fellow sequenced -- and I'm a PhD working in genomics with a lot of contacts -- creating a custom one-off gene therapy solution seems like it would be a very tremendous undertaking.
There is a very difficult problem here in that rare or "personalized" disease treatments are: A) not profitable, so drug companies have no interest, B) there are mountains of paperwork, IRBs, consent waivers, etc, involved in developing an experimental therapeutic, C) by definition you cannot do a proper clinical trial on a one-off, and D) it requires several different types of expertise to pull such a thing off. Sadly this means that it almost never happens, even though I suspect there are a lot of severe and lifelong genetic disorders which could be diagnosed and treated with technology available today.
Based on my experience so far, I suspect that even if you were to hand his physician very strong evidence that "the problem is caused by this specific single mutation", the response will be "OK, thanks". You should not make strong assumptions about them being able to take it from there. All this is based on the best-case scenario of it being a single variant in a coding region; if the disorder is caused by multiple variants at different loci, anything you find will probably not be actionable.
My neurologist ordered sequencing for me from Invitae, to determine the subtype of Ehlers-Danlos I have and rule out neuromuscular diseases. She said insurance usually covers it, and it's only a few hundred bucks if they don't. Invitae appears to do WGS for such panels. I've also heard of Nebula genomics offering affordable WGS and exome sequencing.
She said she'd take a look at the results, and if anything popped out as unusual, I'd see a geneticist.
Identify the molecular pathway involved and see if there's any drugs available that might modulate it in a therapeutic way. You might also identify similar diseases that might share similar treatments, once you know the etiology.
Once a mutation or gene responsible is identified, other patients can be as well, which can slowly lead to mouse models and clinical trials etc.
This. It's not my field but I strongly suspect I have a troublesome mutation of some sort. If I was able to track it down what good would that do? (I almost certainly inherited it which is why I think it's genetic.) Sequencing isn't that expensive these days, I keep thinking about it but even if I found enough others to pin down the mutation what good would that do? "Success" would simply be an accurate diagnosis, nothing more.
Not OP, but I got my whole genome sequenced from sequencing.com. It is currently around 399 USD. The sequencing is done by Nebula Genomics, nebula.org, where it is currently 299 USD.
You get to keep all the raw data from the sequencing and you will get some reports included. I did it in order to do a genetic disease screening as I was very sick with strange symptoms for a long time.
Thanks to you, and others, for sharing. I hadn't yet resorted to looking in the consumer space. In research (and presumably clinical)-land, the costs are substantially higher.
I'll be looking into it further to figure out whether there is some tradeoff here, or if it is just typical cost bloat for medicine/academia.
I haven’t done very thorough research, but my impression is that there is a considerable cost bloat if you go through hospitals and similar, but that the genome sequencing is essentially the same.
Not OP. Last year, Dante Labs ran a deal around the Rare disease day (Feb 28). After submitting my documentation, I got 30x WGS for €260.
As an alternative to step 2, you could also score the filtered vcf file (this is key to get rid of most of the initially millions of variants) with a variant prioritization framework like CADD (cadd.gs.washington.edu) to immediately highlight 'interesting' variants. Highlighting certain genes can definetly help, though it is not always conclusive
(I do not want to demotivate but please be cautious. Even the best analysts have 'only' around 50% case-solve rate. If it is an adult-onset-disease, chances can be lower as the disease mechanism in that case may not be 'consequential' enough to be naturally selected against)
Great guy spotted above :)
Love your offer to help.